Final Report on Process Analytical Technology PAT and Manufacturing Science

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Final Report on Process Analytical Technology
(PAT) and Manufacturing Science
FDA Science Board Meeting 5 November 2004

• Ajaz S. Hussain, Ph.D.
• Deputy Director, Office of Pharmaceutical
  Science, CDER, FDA

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Outline

• Previous FDA Science Board discussion
• Emerging science issues in pharmaceutical
  manufacturing
• Opportunities for improving pharmaceutical
  manufacturing
• The desired state of pharmaceutical
  manufacturing in the 21st Century
• Progress made by the (PAT ) CGMP Initiative
• Continuing the scientific and technological
  progress towards the desired state
• Industrialization dimension of the Critical Path
  Initiative

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Protracted Production Cycle Times
Example(Source G. K. Raju, M.I.T. FDA Science
Board Meeting, November 16, 2001)
4
Resolution of process problems slow/difficult
(Source G. K. Raju, M.I.T. FDA Science Board
Meeting, November 16, 2001)
5
OOS or Exceptions Further Increase Cycle Times
(Source G. K. Raju, M.I.T. FDA Science Board
Meeting, November 16, 2001)
6
Low Process Capability (Source Doug
Dean.PricewaterhouseCoopers. FDA Science Board
Meeting November 16, 2001)
7
New Technologies Dont Use or Dont Tell
(Source Norman Winskill FDA Science Board
Meeting November 16, 2001)
8
Quality by Design A Challenge to Pharma Industry
(Ray Scehrzer, FDA Science Board, 9 April 2002 )
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Quality by Design A Challenge to Pharma Industry
(Ray Scehrzer, FDA Science Board, 9 April 2002 )
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Current State of Pharmaceutical Manufacturing

• Static
• Based predominantly empirical approaches
• Industry reluctant to use new technology
• Fundamental science and engineering principles
  generally less well developed
• High degree of uncertainty that precludes risk
  based (regulatory) decisions
• Manufacturing difficulties
• Very low efficiency and high cost
• May be inadequate to meet future needs

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Technology may not be rate limiting
Steve Hammond, Pfizer
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Technology may not be rate limiting
Wildfong, et al. J. Pharm. Sci. Vol.91, 3 Pages
631-639
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Technology may not be rate limiting
ACPS PAT Subcommittee David Rudd
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Technology may not be rate limiting
Rapid Microbial Methods
S.Lonardi, P.J.Newby, D.Ribeiro, B.Johnson. PAT
Subcommittee meeting October 23, 2002
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Use of new technology may support fundamental
science
Prof. Ken Morris, Purdue University
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Opportunity

• Over the last two decades we have developed or
  utilized methods to solve complex multi-factorial
  problems
• Multivariate empirical methods (e.g., Response
  Surface Methods)
• New measurement, control and information
  technologies
• Improved ability to predict and assure quality
  performance
• Regulatory utility of fundamental science and
  engineering principles is likely to accelerate
  development of these principles

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Challenge

• Scientific information related to pharmaceutical
  product/process development is often filtered out
  of CMC sections of regulatory submissions
• regulatory uncertainty
• fear delayed approval
• High degree of uncertainty precludes risk based
  decisions
• Culture organizational barriers

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Overcoming the Challenge

• Incentive for companies that acquire extensive
  understanding about their product and
  manufacturing process and share this with the
  regulators
• Enhanced science and risk-based regulatory
  quality assessment will be possible
• Setting specifications
• Reduction in the volume of data to be submitted
  replaced by more knowledge based submissions,
• Flexible post approval change management -
  continuous improvement

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Overcoming the Challenge

• Understand and define the problem
• Ensure current regulations and policies
  facilitate innovation and continuous improvement
• Overcome cultural organizational barriers-
  turf issues
• Develop new policies and procedures
• Ensure FDA staff are trained and work as a team
  to address review and inspection issues

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Understand and define the problemIn absence of
relevant information

• Conditions used (e.g., mixing time) for clinical
  materials become regulatory commitments
• Process control is predominantly based on
  documented evidence of conformance to SOP's
• Generally includes fixed process conditions and
  laboratory based testing of in-process materials

21
Understand and define the problemIn absence of
relevant information

• Acceptable quality characteristics, or
  specifications, are generally described in terms
  of discrete or attribute data
• e.g., pass/fail or no unit outside 75-125
  (n30)
• Rate of failure increases with increasing
  sample size drives the industry to minimalist
  testing schemes and discourages collection of
  information

22
Understand and define the problemIn absence of
relevant information

• Material characteristics (e.g., excipients) and
  their relation to process-ability are not well
  understood
• Variability in (physical) material
  characteristics, fixed process conditions (e.g.,
  time), testing approaches that do not provide
  robust estimates of variability and complex SOPs
  can lead to frequent deviations and out of
  specification (OOS) observations

23
Understand and define the problemIn absence of
relevant information

• OOS investigations take significant (time)
  resources and have a low rate of success for
  preventing recurrences batches have to be
  rejected (internal failure) due to an inability
  to document quality
• Low efficiency and costs associated with
  manufacturing far exceed those for RD operations
  in innovator pharmaceutical firms

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Understand and define the problemIn absence of
relevant information

• Test to test comparison is the only available
  option for validating new tools and technology
• New control systems (dont tell mode) are
  additional methods and companies still have to
  continue USP or regulatory testing
• Post approval changes generally require
  regulatory notification and in many cases prior
  approval

25
Current regulations and policies facilitate
innovation and continuous improvement

• Regulations are generally broad and flexible
• Exception CFR Part 11?
• However, current regulatory practices and
  procedures reflect the current state of
  information in submissions
• Process validation inspection
• CMC review

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Overcome cultural organizational barriers-
turf issues A Shared Vision for the 21st
Century

• Reason to change current state is untenable
• Need to facilitates innovation and continuous
  improvement in the interest of public health
• Opportunities for continuous learning and
  professional development
• Articulate the desired state for 21st Century
  pharmaceutical manufacturing
• Presented to the FDA Science Board (April, 2002)

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The PAT Team Teambuilding (the engine of success)

• A systems approach for regulatory assessment of
  PAT applications
• PAT Team for CMC review and CGMP inspection was
  created
• A comprehensive scientific training program was
  developed
• University of Washington, Seattle National
  Science Foundation (NSF) Center for Process
  Analytical Chemistry
• Purdue University NSF Center for Pharmaceutical
  Process Research
• University of Tennessee NSF Measurement Control
  Engineering Center

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Desired State Manufacturing

• As adopted by the International Conference on
  Harmonization (ICH)
• Product quality and performance achieved and
  assured by design of effective and efficient
  manufacturing processes
• Product specifications based on mechanistic
  understanding of how formulation and process
  factors impact product performance
• An ability to affect continuous improvement and
  continuous "real time" assurance of quality

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Desired State Regulatory

• Regulatory policies and procedures tailored to
  recognize the level of scientific knowledge
  supporting product applications, process
  validation, and process capability
• Risk based regulatory scrutiny that relates to
  the level of scientific understanding of how
  formulation and manufacturing process factors
  affect product quality and performance and the
  capability of process control strategies to
  prevent or mitigate risk of producing a poor
  quality product

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FDA Definition of PAT (now also ASTM ICH
definition)

• A system for designing, analyzing, and
  controlling manufacturing through timely
  measurements (i.e., during processing) of
  critical quality and performance attributes of
  raw and in-process materials and processes with
  the goal of ensuring final product quality

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Removing the Obstacles

• Guidance for Industry
• PAT A Framework for Innovative Pharmaceutical
  Development, Manufacturing, and Quality Assurance
  (Final, September 2004)
• A framework for supporting innovation in the
  interest of the public health not a how to
  guidance
• Removes regulatory uncertainty
• Supported by the PAT Team approach (review,
  compliance, and inspections) and ASTM
  International (E55)
• Emerging infrastructure in the pharmaceutical
  community
• EU PAT Team,.

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ICH Q8 Pharmaceutical Development

• Currently being developed and is expected to
  reach the ICH Step 2 in November 2004.
• Creates an opportunity for an applicant to
  demonstrate an enhanced knowledge of product
  performance over a wider range of material
  attributes (e.g. particle size distribution,
  moisture content, and flow properties),
  processing options and process parameters.

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Summary Through the CGMP Initiative FDA was able
to

• Understand and define the problem
• Establish a sense of urgency
• Create a powerful guiding coalition
• Develop a vision desired state
• Communicate and build consensus on the desired
  state
• Remove obstacles
• Plan for short term wins
• Take steps towards anchoring changes in the
  corporate culture and the pharmaceutical community

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Created opportunities for significant cost
savings

• Efficiency improvements estimated to save
  billions of dollars every year
• 15-50 billion every year in US as a result of
  the FDA Initiatives (Prof. Jackson Nickerson,
  Washington University in St. Louis)
• World-wide cost-savings from efficiency
  improvement is suggested to be 90 billion each
  year (Benson and MacCabe. Pharmaceutical
  Engineering, July 2004).

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Preparing for the future

• In the future, pharmaceutical manufacturing will
  need to employ innovation, cutting edge
  scientific and engineering knowledge, and the
  best principles of quality management to respond
  to the challenges of new discoveries
• Complex drug delivery systems and nanotechnology
• Individualized therapies or genetically tailored
  treatments.

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The Critical Path Initiative

• Industrialization dimension
• Strengthen Quality Clinical connection
• Sound scientific approaches for calibration and
  validation of new technologies
• Encourage development of fundamental science and
  engineering principles
• E.g., material (nano-materials) science and
  processing
• Support the US pharmaceutical academic programs

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Thank you

• FDA Science Board
• Advisory Committee for Pharmaceutical Science
• PAT Subcommittee
• Manufacturing Subcommittee
• Others